IVF – A blessing or a bane?

Many patients who have been advised IVF treatment wonder if they will have a normal baby at the end of it and if the IVF carries higher risk of certain disorders. Education from credible and scientific sources helps bust several myths on this subject.

As an IVF specialist I often come across questions from my patients about safety of IVF procedure and the well being of the offspring resulting from IVF. Many patients ask me if the IVF baby could, in any way, be different from a normally conceived baby, and are, at times, reluctant to undergo the fertility treatment. Many of these patients quote some horror stories of other patients who have undergone IVF.

What I explain to the patients is that most of the times they get to hear just one side of the story. I try to make them understand that IVF is a medical procedure used to help couples conceive who find it difficult to conceive for several biological reasons. Just like all other medical interventions, IVF also has its own set of disadvantages, and can, at times, cause inconvenience to women undergoing treatment.

If you have been recommended to undergo IVF as the best way to conceive, I suggest you  not to form any preconceived opinions about the procedure based just on hearsay. Instead, you should discuss the pros and cons of the procedure, possibility of its success and chances of any inconvenience etc with your treating specialist and to educate yourself about the science behind the procedure from authentic sources. As Benjamin Franklin once said – “An investment in knowledge pays the best interest”!

I will continue to write on this subject to answer some frequently asked questions and address the common myths about fertility treatment, specially using IVF. Do write to me at ivfgurgaon@gmail.com if you have any questions about IVF.

Five frequently asked questions about genetics of Recurrent Pregnancy Loss

Miscarriage is a very traumatic experience for any woman or couple and can often mean loss of hope for couples finding it difficult to conceive. Recurrent miscarriages, also known as Recurrent Pregnancy Loss (RPL) is naturally even more distressing and worrisome for the affected couples. While a lot about the causes and reasons for RPL still remains mystery, we know that genetic factors play a significant role in causation of RPL. This aspect of RPL is not generally well understood by the affected couples owing to the complex science behind the same. This article is an effort to explain the genetics of RPL in simple language to bridge the gap in knowledge for the common people on this subject.

Over last ten years, I have consulted and counselled hundreds of couple who have suffered pregnancy loss, either in form of miscarriages or stillbirths. Miscarriage (also known as pregnancy loss) is a relatively common problem encountered in up to 15 to 25 % of all clinically recognized pregnancies, and in many of these cases the actual cause of pregnancy loss remains unidentified.

Most of the miscarriages are sporadic in nature and can be attributed to defects within the fetus. However, some woman may lose their pregnancy repeatedly. Recurrent pregnancy loss (RPL) is defined as loss of three or more consecutive clinically recognized pregnancies and affects around 1% of couples actively trying to conceive. RPL causes significant anxiety for the suffering patients, especially for the pregnancies resulting from fertility treatment. In addition, RPL in patients undergoing fertility treatment also causes significant financial stress for the couple.

Both Maternal age and number of previous miscarriages independently increase the risk of miscarriage in the subsequent pregnancy. However patients with RPL still have a remarkably good prognosis for live births. Also, the overall incidence of pregnancy loss with IVF pregnancy is almost same as in wider population.

The real cause of RPL remains unknown in up to 50% of the women, despite of all the advancements in diagnostics. The known causes of RPL include –

  1. Genetic Causes
  2. Immune Causes
  3. Anatomical Causes
  4. Hormonal Causes
  5. Environmental and occupational causes

While genetic abnormalities in the fetus are known to cause up to 50% of sporadic early pregnancy losses, only about 2 to 5% cases of RPL can actually be attributed to genetic abnormalities in the fetus. In this article, I will focus only on  understanding of genetics of reproduction and genetic causes of RPL. I will discuss other causes and management of RPL in my upcoming posts.

Here are five things you need to know about the genetic causes of RPL

  1. What is a chromosome?

The basic genetic unit of human body is “DNA”, which is packed together to form “Gene”. Genes are the working sub-units of DNA and carry the information that determines the features or characteristics passed on from one generation to another. Human beings are estimated to have between 20,000 to 25,000 genes. Genes are located inside the nucleus of cells and are found on thread like structures, known as which are the “Chromosomes”.

Chromosomes are arranged in pairs inside nucleus of the cells. Each human cell normally contains 23 pairs of chromosomes, with one chromosome of each pair inherited from one of the parents. The first twenty two pairs of chromosomes are same in both men and women, and are known as “Autosomes”. The 23rd pair is known as the “Sex chromosomes” and is   identified as either “X” or “Y” chromosome. The type of sex chromosome determines the gender of the person, with females having two X chromosomes and males having one X and one Y chromosome.

Every person has got 2 copies of each gene, one inherited from each parent. While most of the genes are same in all individuals, a small number of genes (< 1%) are unique for each individual and these genes eventually make all human beings individual.

  1. What is cell division?

In order to grow and reproduce the cells have to continuously divide to produce “daughter cells”. This cell division can be of two types- mitosis or meiosis. Without getting into technicalities, it would suffice here to know that the sex cells (both male and female) divide by meiosis and one cell produces four cells (known as gametes – eggs in women and sperms in men) at the end of the division.

  1. How is the fetus formed?

An embryo is formed when the egg and sperm meet each other and the sperm penetrates the wall of the egg, thus bringing its own genetic material into the genetic material of the egg. This process, known as fertilization of the egg, produces a cell with full set of genetic material (23 pairs of chromosomes) for the offspring. The embryo thus formed multiplies repeatedly and very quickly to create a mass of cells, which then differentiate to form different organs of the future baby.

  1. What are common genetic anomalies which can cause RPL?

A variety of genetic factors can cause pregnancy loss. The commonly known causes include-

  1. Aneuploidy- an extra number of chromosome
  2. Translocation and inversion of chromosomes- fault in structure of chromosome
  3. Deletion or duplication of chromosome- fault in amount of DNA in a chromosomes
  4. Single gene mutations- chromosomal abnormality at the level of genes

Aneuploidy – Aneuploidy is an error of cell division, which results in the “daughter” cells having wrong number of chromosomes. In some cases there is a missing chromosome, while in other cases, there is an extra chromosome inside the cell. Thus, such individuals with aneuploidy may have cell with 45, 47, or 48 chromosomes. Such individuals will have cells with improper genetic information, which can result in miscarriages. In some cases with aneuploidy (as in cases of Down’s syndrome), the fetus may survive but the child is likely to be born with various abnormalities. The most common aneuploidies are extra chromosome number 16, 18, 21.

Translocation – In translocation, a segment from one chromosome is transferred to another chromosome or to a new site on the same chromosome. Translocation could either be non-reciprocal, in which there is a one way migration of chromosomal segment or reciprocal, which involve exchange of segments from two different chromosomes. Translocation leads to alteration in the alignment of the genetic structure of the fetus and could, in some cases, result in miscarriage.

Inversion – An inversion is a chromosomal rearrangement in which the affected segment of a chromosome is reversed end to end, and typically occurs when a single chromosome undergoes breakage and rearrangement within itself.

Inversions and translocations may not cause any genetic abnormalities in carriers (parents), as long as the rearrangement is balanced with no extra or missing DNA. However, the gametes (eggs and sperms) in affected people carry unbalanced (excess or insufficient) amount of genetic material. The resultant pregnancy is, therefore, genetically abnormal and can lead to infertility, recurrent miscarriages and sometimes increased risk of cancer.

Deletion and Duplication of Chromosomes – In deletion, a portion of the chromosome is missing or deleted, whereas in duplication, a portion of the chromosome is duplicated, resulting in extra genetic material. Both these genetic abnormalities can lead to various kinds of syndromes in the offspring.

Single gene mutation – Single gene mutations are caused  by DNA alterations within one particular gene. These mutations can affect the mother or the fetus.

Mutations in the mother can interfere with implantation of the fetus, thus causing infertility or recurrent miscarriage. Some examples of maternal single gene disorders include maternal myotonic dystrophy, connective tissue disorders like Marfan Syndrome and Ehler Danlos Syndrome and sickle cell disease.

Single gene mutations in fetus, which could lead to RPL include autosomal dominant lethal skeletal dysplasia, Type 2 osteogenesis imperfecta, autosomal recessive disorders like Alpha Thalassemia and X chromosome linked disorders which typically are lethal in male fetus.

  1. What are chance of live birth after RPL

The chances of having a live birth after recurrent miscarriages are not as grim as they appear. The overall probability of live birth after RPL for women aged between 30 and 34 years of age is approximately 66- 70%. The probability, however, goes down with each extra pregnancy loss beyond 3 and increasing maternal age. Newer technologies like “Preimplantation Genetic Diagnosis” (PGD) can help in improving the chances of live birth in couples with known genetic disorders, as it helps in selecting the embryos with the correct genetic composition before transferring into the uterus.

Thorough evaluation of couples who have already encountered miscarriages in two consecutive pregnancies is recommended, because the risk of another miscarriage after 2 lost pregnancies is already almost 30% compared with a risk of miscarriage of 33% after 3 lost pregnancies.

Please write to me at ivfgurgaon@gmail.com if you have any questions related to RPL or if you need more information on this subject.

Seven frequently asked questions on “Poor Ovarian Reserve”

Poor ovarian reserve is a major cause of reduced fertility among women who delay planning a family. Many of these women remain unaware of this reality and dont know that there was means to preserve their eggs for a delayed child bearing.

Ovarian Reserve is one of the more frequently discussed topic in my infertility practice, especially as many working women plan to defer child bearing while they remain worried about their fertility potential in future. Besides this, I see a lot of women who are not able to conceive and have poor ovarian reserve. Here are seven most frequently asked questions related to “Ovarian Reserve” and my answers to these.

  1. What is ovarian reserve?

Ovarian reserve of a woman is defined as an estimated number of oocytes/ eggs a woman has in her ovaries at a given time. A female fetus has a maximum of 6 to 7 million eggs at 16 to 20 weeks of gestational age. Thereafter, this number keeps on declining and reaches an approximate count of 1 to 2 million eggs at the time of birth, and further falls to approximately  250,000 to 500,000 eggs at puberty. This count further declines to approximately 25,000 at around 37 years of age and to less than 1000 at menopause.

  1. How is ovarian reserve estimated?

There are various tests to assess ovarian reserve. The main tests include –

  1. Serum FSH/LH- done on the 2nd /3rd day of a woman’s menstrual cycle gives an indication of the woman’s egg reserves.
  2. Serum Anti mullerian hormone (AMH) – very sensitive test of testing a woman’s ovarian reserve. It can be done on any day of the menstrual cycle.
  3. Antral Follicle count-  Antral follicle are small follicles present in the ovary that are best seen during the early phases of the menstrual cycle. Transvaginal ultrasound (TVS) of the pelvis is used to count the number of antral follicles, which gives good estimate of the woman’s ovarian reserve.AFC

    3.  Why is testing for ovarian reserve important?

A woman’s ovarian reserve is an indicator of her fertility potential. Women facing difficulty in  conception or planning to delay child bearing should be assessed for their ovarian reserve for timely and appropriate fertility intervention.

  1. What is poor ovarian reserve?

If a woman has a premature decline in her egg quantity due to any reason which reduces her chances of having a mature egg, she is suspected to have “poor ovarian reserve”. It is natural for the number of eggs present in a lady to decline as she ages – both due to ovulation and a natural cell death process called “Apoptosis” – and normally the woman would exhaust her egg reserve by the time she reaches menopause. But, if the decline in egg count happens faster than that and the woman is depleted of her egg reserve before expected menopause, she should be suspected to have “poor ovarian reserve”.

  1. What causes poor ovarian reserve?

Poor ovarian reserve can be caused by a number of reasons-

  1. Genetic defects including chromosomal anomalies such as Turner’s syndrome and gene defects like Fragile X syndrome.
  2. Damage to the ovaries due to any injury, torsion, infection, surgery or due to radiation or chemotherapy.

However in most cases the exact cause of poor ovarian reserve remains unknown.

  1. Does poor ovarian reserve lead to reduced chances of pregnancy?

Poor ovarian reserve is associated with reduced chances of pregnancy both naturally and following fertility treatment. This is because the number of eggs is reduced which corresponds to reduced chances of pregnancy. The goal of ovarian reserve testing is to identify those individuals who are at risk of diminished ovarian reserve so that they can be encouraged to pursue more aggressive treatment to achieve pregnancy.

  1. Is there any treatment to improve the ovarian reserve?

There are no concrete remedies to improve Ovarian reserve however lately some medications have been developed  to improve the egg quality and number. The benefits of these medicines are not yet conclusively proven.

preventing failure

You can read more about management of Poor Ovarian Reserve at http://www.slideshare.net/DrParulKatiyar/management-of-poor-ovarian-reserve-dr-parul-katiyar

Dr Parul Katiyar 

For more information on poor ovarian reserve and ways to address poor fertility resulting from this, please write to me at ivfgurgaon@gmail.com.

 

IVF treatment and twins – role of multiple embryo transfer

One of my patients whom I was counselling for IVF treatment for her primary infertility recently asked me a very basic question about the procedure and its outcome. She asked me – “Doctor, can I conceive only twins with IVF?”. This again prompted me to think about this very important aspect of fertility treatment – the risk of multiple pregnancy resulting from multiple embryo transfers. Some big celebrities like Celine Dion, Julia Bradbury and Jennifer Aniston and our own Farah Khan have been in news for conceiving multiple babies with IVF and that somehow makes many women undergoing IVF treatment to think that IVF produces multiple pregnancy only.  In this post, I  will try to explain the reasons for multiple pregnancies resulting from IVF treatment and how can this be avoided.

According to global evidence, approximately 25% of total births resulting from ART treatment are twins, a rate much greater than in the general population (approximately one in 80 births). The incidence of triplets and quadruplets is also high among pregnancies resulting from IVF treatment. However, the majority (approx. 70%) of pregnancies resulting from IVF treatment are singletons. With an ever increasing focus on optimizing treatment outcome and reducing complications associated with IVF treatment, the risk of multiple pregnancies with IVF has become  one of the most important considerations while planning the IVF cycle.

The process of implantation of an embryo in the womb is a complicated one and we still do not know what transpires between the embryo and the uterus when they come in contact with each other, and therefore, we do not completely understand the reasons for a positive or negative pregnancy outcome also. Since there is no test or procedure that can assure pregnancy with IVF – an expensive treatment not generally covered by insurance policies – the physicians naturally want to enhance the probability of pregnancy and consider putting in more than one embryos. The risk of multiple pregnancy in IVF cycle derives from this tendency among treating physicians to transfer more than one embryos inside the uterus in order to increase the odds of pregnancy.

Pregnancy rates with IVF treatment appear to peak with transfer of three or four embryos. However, the risk of multiple pregnancy also increases at the same time. Multiple pregnancy is associated with   a higher rate of maternal, fetal and neonatal complications and is considered as the single biggest risk or complication of fertility treatment.

Good practice in IVF treatment aims to reduce the risk of multiple pregnancy whilst maximizing the overall chances of conception. This is achieved by proper patient selection and counselling.

  1. Young women who have the best chance of conception, also have the highest chance of conceiving multiples. Therefore, I always offer them a single embryo transfer at a time and freeze the rest of the good quality embryos for later use.
  2. An extended culture of embryos up to the day 5, called as blastocyst culture, helps in better embryo selection for transfer into the uterus. I advise blastocyst culture for patients with more than 3 good quality embryos and transfer a single blastocyst in such patients.

I also believe that treating physicians should counsel the patients that only success parameter in any IVF cycle is a healthy baby born to a healthy mother and reducing the number of embryos transferred in a cycle is a significant step to achieve that goal. Patients should be counselled about the risk associated with transferring many embryos and also explained that freezing the spare embryos and transferring them in subsequent cycles if needed  would give them even better cumulative pregnancy outcome than putting back many embryos in one embryos transfer.

Please contact me at ivfgurgaon@gmail.com for any queries related to IVF or any aspect related to infertility treatment.

Does infertility treatment put women at higher risk of cancers?

Many patients ask me if IVF treatment leads to a higher risk of cancers, especially in breasts and ovaries. As per the latest published scientific literature on this subject, there is no real evidence to link IVF with higher risk of cancers among these women.

As an infertility specialist, I am required to counsel mcancery patients about potential complications of fertility treatment. One of the most often asked question is if infertility treatments put the women at a higher risk of cancers.

Fertility drugs like clomiphene citrate and hormones used for ovarian stimulation & assisted reproductive technologies like IVF and ICSI have all been implicated to causes various cancers among women, including not only cancers of cervix, uterus, ovaries and breast, but also melanoma and cancers of the central nervous system.

A simple answer to this question is that as per the latest studies, there is no conclusive evidence to suggest a higher risk of invasive cancers in women receiving infertility treatment.

Why has infertility treatment been linked with higher risk of cancers?

There are multiple theories as to why fertility treatment may increases the risk of cancer in women.

  1. Hormonal treatment with Clomiphene and Gonadotropins causes cancers because elevated levels of estrogen and progesterone hormones can trigger carcinogenic activity in the ovarian , uterine and breast tissues
  2. Ovarian enlargement due to development of multiple follicles causes trauma to the ovaries, which may result in carcinogenesis.
  3. Injury to ovaries resulting from multiple needle punctures made during egg retrieval has also been suggested to cause cancers of ovaries.

However, at the same time, it has also been suggested that infertile and nulliparous women are inherently at an increased risk of certain cancers so actually infertility treatment may not be the cause of cancers in these women.

What does the scientific evidence tell us?

Extensive research has been conducted on this subject, but the results so far have been pretty inconclusive. We need to appreciate that it is indeed difficult to study direct relationship between cancers in women and infertility treatment because many of these cancers appear many years after the treatment/ causative injury. Therefore, large populations have to be studied over a long period of time in order to arrive at any meaningful conclusions regarding the relationship between fertility treatment and cancers.

Of all the cancers suspected to be associated with infertility treatment, cancers in ovaries are most often linked to the infertility treatment. The overall evidence in this regard is mixed. While some studies have found the risk of ovarian cancers to be higher in women with a history of fertility treatment, others have ruled any such association out.

A research group from Israel retrospectively studied possibility of such an association in over 106,000 women, who had delivered between 1998 and 2013.1 The researchers found that women with conceived with IVF treatment had a significantly increased risk of being diagnosed with ovarian and uterine cancers as compared to women who had conceived either naturally or using ovulation induction. However, another study of over 87,000 women from Israel only conducted around the same time did not find any significant relationship between IVF exposure and risks of breast, endometrial, or ovarian cancers.2

In a population based cohort study of 812,986 women from Norway, who had delivered between 1984 and 2010, the researchers tried to assess the overall risk of cancers and specifically of cancers of cervix, uterus, ovary, thyroid, the central nervous system and melanoma among the women who had conceived using ART. 3 They found that the overall risk of cancers was not higher among the women conceiving using ART and delivering at least one baby. Although there was a hint of higher incidence of some cancers among women undergoing IVF, this could not be statistically proven owing to the weak nature of this kind of population based study.

A Cochrane review of 25 studies (consisting of 11 case-control studies and 14 cohort studies) covering 182,972 women did not find any convincing evidence supporting an increased risk of invasive ovarian tumors with fertility drug treatment. However, the researchers concluded that there may be an increased risk of borderline ovarian tumors in subfertile women treated with IVF.4

Cancer of the breast is the second most commonly discussed cancer that is assumed to be linked with hormonal treatment for infertility. Large studies and meta-analyses have not found any significant correlation between treatment for infertility and breast cancer. 5,6 While some studies have suggested that the risk of breast cancer increases after exposure to ovulation inducing agents (especially clomiphene citrate)6, many other studies do not support such an association.5 Therefore, I don’t advocate long term administration of Clomiphene, as the risk of breast cancer is not fully ruled out with its long term use.

Conclusion

Overall we can say that on the basis of existing scientific evidence, there is no conclusive proof of a causal link between ovarian and breast cancers and fertility treatment. Therefore, treatment of infertility using hormones and ART is by and large safe. The cancers of ovary and breast detected among women with history of treatment for infertility are more likely to be related to their infertile status than to the effect of fertility drugs. However, we must keep in mind that majority of the available studies on this subject suffer from methodological limitations and therefore cannot be fully relied upon. Further research on this subject will certainly enlighten us more on the possibility of any such association.

References

1.       The risk of female malignancies after fertility treatments: a cohort study with 25-year follow-up. Kessous et al. J Cancer Res Clin Oncol. 2016 Jan;142(1):287-93.

2.       In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Brinton et al. Fertil Steril. 2013 Apr;99(5):1189-96.

3.       Cancer risk among parous women following assisted reproductive technology. Reigstad et al. Hum Reprod. 2015 Aug;30(8):1952-63.

4.       Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Rizzuto I, Behrens RF, Smith LA. Cochrane Database Syst Rev. 2013 Aug 13;8:CD008215.

5.       IVF and breast cancer: a systematic review and meta-analysis. Sergentanis et al. Hum Reprod Update. Sergentanis et al. 2014 Jan-Feb;20(1):106-23.

6.       Breast cancer incidence after hormonal treatments for infertility: systematic review and meta-analysis of population-based studies. Gennari et al. Breast Cancer Res Treat. 2015 Apr;150(2):405-13.

For further information or queries on this subject, please write to me at ivfgurgaon@gmail.com.

Dr Parul Katiyar

Making IVF Patient Friendly with Milder Stimulation

It is time to adopt more physiological and patient friendly ovarian stimulation strategies for IVF, which require lesser amount of hormonal stimulation and still produce 2-3 follicles for IVF. Such minimal/ mild stimulation protocols should preferably be used in the modern infertility practice.

There has been good debate on what is the correct number of eggs to be retrieved and number of embryos to be transferred during an IVF cycle. The debate revolves around success rate and cost of the procedure and patient comfort and compliance. I will try to address the first of these two questions, i.e. whats is a good number of eggs to retrieve during an IVF cycle and how should one go about it.

Technically speaking, a single egg has the potential for fertilization and the first IVF baby was born from a natural cycle IVF. But, not every egg gets fertilized on being exposed to sperms and not all embryos have the potential to result in a pregnancy. This inherent failure of assurance of pregnancy resulting from the transfer of a single embryo (fertilized egg) after IVF has resulted in evolution of the practices of artificially inducing the ovaries to produce many eggs in a cycle and of transferring more than one embryo into the uterus. However, even these interventions do not guarantee success of the IVF cycle and the outcome of such IVF cycles can also be measured only in terms of probability.

What is the standard IVF practice?

The standard practice is to give daily hormonal injections to induce the growth of many eggs (targeted number of eggs varies from 5-6 to up to 10), which is coupled with strict monitoring using ultrasounds and blood tests. This process is often very stressful and unfriendly for the patient. This also entails a risk of some complications due to the stimulation which can be short term and may have some long term sequel as well.

What are the disadvantages of conventional stimulation protocols for IVF?

The conventional stimulation protocols have following disadvantages-

  1. Patient discomfort associated with daily injections
  2. Risk of complications like ovarian hyperstimulation, which occurs as a result of recruitment of excessive number of follicles.
  3. In patients with poor ovarian reserve, higher dosage of hormones may not yield more eggs because stimulation helps in recruitment of follicles already present in the ovaries.
  4. Quantity does not correlate with quality – Retrieval of a larger no of eggs may not necessarily mean better quality of eggs. In fact, many of these eggs may be of poor quality and some may even have aneuploidy.
  5. Excessive production of hormone Estradiol (produced by a larger no of growing follicles) has a negative impact on the endometrial receptivity, i.e. the ability of endometrium to allow implantation of the embryos. This may negatively affect the outcome of the cycle.

 

Standard ovarian stimulation – Growth of multiple follicles

What is minimal/ mild stimulation IVF?

Minimal/ mild stimulation strategy aims to optimally stimulate the ovaries to produce a few (typically 2-7) follicles, rather than bombarding them with hormones in order to produce a larger numbers of follicles. This strategy yields a smaller no of follicles, but these follicles are optimally primed to grow and are likely to be healthier. These protocols use either only oral medications or a combination of oral medications and lower dose of hormones given for a shorter duration. Mild stimulation strategies are specially beneficial for IVF in women, who are at higher risk of hyper-stimulation or are known poor responders.

What are the advantages of minimal/ mild stimulation IVF?

Minimal/ mild stimulation IVF, sometimes also called as micro IVF or mini IVF offers several advantages to select group of patients. These include-

  1. The minimal/ mild stimulation protocols are more patient friendly as they require relatively lesser medical intervention.
  2. Minimal/ mild stimulation is more physiological and in sync with woman’s natural cycle.
  3. Growth of lesser number of follicles means a less steep rise in the levels of hormone Estradiol, as a result of which endometrium is likely to be more receptive, thus achieving good pregnancy rate despite of lesser number of eggs.
three follicles
Minimal ovarian stimulation – growth of three follicles

This is the time to reconsider ovarian stimulation strategies for IVF, so that a good pregnancy rate can be balanced with more physiological and patient friendly treatment.

Further Readings

1. http://humrep.oxfordjournals.org/content/25/11/2678.full

2. http://www.ncbi.nlm.nih.gov/pubmed/19091754